Treatment of sexual dysfunction in certain patient groups

ABSTRACT

Methods for treating specific patient groups for sexual dysfunction are provided. The methods of the present invention comprise the utilization of pharmaceutical compositions in patients who are free of cardiac disease and/or who have not been given organic nitrates.

FIELD OF THE INVENTION

[0001] The present invention provides relates to methods for thetreatment of sexual dysfunction in males and females (including but notlimited to erectile dysfunction in males) in particular treatmentgroups. The methods of the present invention comprise the utilization ofpharmaceutical compositions to patients who are free of symptoms ofcardiac disease and who have not been treated with drugs which causehypotensive effects, such as nitrites and nitrates.

BACKGROUND

[0002] Impotence or erectile insufficiency is a widespread disorder thatis thought to affect about twelve percent of adult men under ageforty-five, about twenty percent of men at age sixty, and aboutfifty-five percent of men at age seventy-five.

[0003] There is more than one cause of erectile dysfunction. Forexample, erectile dysfunction can be psychological, resulting fromanxiety or depression, with no apparent somatic or organic impairment.Such erectile dysfunction, which is referred to as “psychogenic”, isresponsible for about fifteen to twenty percent of cases of impotence.In other cases, the erectile dysfunction is associated withatherosclerosis of the arteries supplying blood to the penis; suchdysfunction is referred to as “arteriogenic” or “atherosclerotic.” Aboutforty to sixty percent of cases of impotence are arteriogenic in origin.

[0004] In still other cases, there is leakage from veins in the penissuch that sufficient pressure for an erection can be neither obtainednor maintained. This dysfunction is referred to as “venous leakage,” or“abnormal drainage”. This condition is often exacerbated by the presenceof some arteriogenic dysfunction whereby the supply of blood to thepenis is impaired. In still other cases, the dysfunction is associatedwith a neuropathy, such as nerve damage arising from, for example,surgery or a pelvic injury, in the nervous system affecting the penis.Such a dysfunction is referred to as “neurogenic” and this accounts forabout ten to fifteen percent of cases of impotence.

[0005] There is also a high incidence of erectile insufficiency amongdiabetics, particularly those with insulin-dependent diabetes mellitus.Erectile dysfunction in diabetics is often classified as “diabetogenic,”although the underlying dysfunction is usually neurogenic associatedwith neuropathy, but may be arteriogenic or neurogenic and arteriogenic.About half of diabetic males suffer from erectile insufficiency, andabout half of the cases of neurogenic impotence are in diabetics.

[0006] Additionally, erectile insufficiency is sometimes a side effectof certain drugs, such as beta-blockers that are administered to reduceblood pressure in persons suffering from hypertension, or drugsadministered to treat depression or anxiety. Excessive alcoholconsumption has also been linked to erectile insufficiency. These formsof erectile insufficiency may be regarded as a subset of neurogenic orpsychogenic insufficiency.

[0007] A number of methods to treat impotence are available. Thesetreatments include pharmacological treatments, surgery and, in cases ofpsychogenic dysfunction, psychological counseling is sometimeseffective. Psychogenic impotence often can be cured by counselingcoupled with a demonstration to the patient that he is capable of havinga full erection by inducing such an erection one of a few times in thepatients. Insufficiency due to excessive alcohol consumption issometimes cured by reducing or elimination such consumption.

[0008] In the rare cases, where the insufficiency is physical because ofvenous leakage, surgery can usually be employed to repair the venouslesion and thereby either cure the insufficiency or, if there remains anerectile insufficiency after repair of the venous lesion, render theinsufficiency amenable to treatment by pharmacological methods. Also,penile implants, which provide a mechanical means to produce an erectionsufficient for vaginal penetration, are widely used to treat impotence.In recent years, implants have been employed, especially in cases wherepharmacological intervention is ineffective, which are usually cases ofsevere atherogenic impotence. Treatment of impotence with penileimplants, however, entails serious disadvantages. Such treatmentrequires surgery and necessitates total destruction of the erectiletissues of the penis, forever precluding normal erection.

[0009] Pharmacological methods of treatment are also available. Suchmethods, however, have not proven to be highly satisfactory and can beaccompanied by severe side-effects. Papaverine is now widely used totreat impotence, although papaverine is ineffective in overcomingimpotence due, at least in part, to severe atherosclerosis. Papaverineis effective in cases where the dysfunction is psychogenic or neurogenicand severe atherosclerosis is not involved. Injection of papaverine, asmooth muscle relaxant, or phenoxybenzamine, a non-specific blocker andhypotensive, into a corpus cavernosum has been found to cause anerection sufficient for vaginal penetration. Also, in cases where severeatherosclerosis is not a cause of the dysfunction, intracavernosalinjection of phentolamine, an α-adrenergic blocker, causes an erectionsufficient for vaginal penetration. The resulting erection is one ofsignificantly shorter duration than that induced by intracavernosalinjection of papaverine or phenoxybenzamine and is of such shortduration that satisfactory sexual relations are difficult or impossible.

[0010] Treatment of impotence with papaverine or phenoxybenzamine oftenresults in priapism, a locking-up of an erection for a long period oftime, typically a few hours and sometimes longer than twenty-four hours.Priapism is a serious, deleterious side effect of treatment of erectileinsufficiency with these drugs. Beyond the embarrassment that may becaused for some men, priapism is usually painful, irreversibly damageserectile tissue, and, to be relieved, requires bleeding orpharmacological intervention, such as injection of a sympathomimeticdrug, such as adrenaline.

[0011] Even if priapism does not occur with use of papaverine, such useis associated with a painful, burning sensation in the first two or sominutes after the injection and there are indications that repeated useof papaverine causes undesirable, extensive intracavernous fibrosis.Further, as indicated above, impotence arising from severeatherosclerosis is not susceptible to treatment with papaverine,phenoxybenzamine, phentolamine or papaverine together with phentolamine.In any case, phenoxybenzamine is not suitable for use in treatingimpotence because it is a carcinogen.

[0012] Thus, although impotence is a ubiquitous problem, there are fewsatisfactory methods available for treating this disorder. Because ofthe relatively invasive intervention involved and the high failure rateof penile prostheses, surgical approaches provide unattractivealternatives. A safe pharmacological approach to the treatment ofimpotence is still to be achieved.

[0013] What is needed is a pharmaceutical that is effective but lackingin significant side effects.

SUMMARY OF THE INVENTION

[0014] The present invention provides relates to methods for thetreatment of sexual dysfunction in males and females (including but notlimited to erectile dysfunction in males) in particular treatmentgroups. The methods of the present invention comprise the utilization ofpharmaceutical compositions to patients who are free of symptoms ofcardiac disease and who have not been treated with drugs which causehypotensive effects, such as nitrites and nitrates. The compositionscomprise quinolines and quinolones, including derivatives thereof.

[0015] It is not intended that the present invention be limited by thenature of the derivative. In one embodiment, the present inventioncontemplates halogenated quinolines (e.g., bromoquinoline) andisoquinolines (e.g., 1-methylisoquinoline and 5-nitroisoquinoline). Inanother embodiment, the present invention contemplates halogenatedquinolones (e.g., flosequinolone). In a preferred embodiment, thequinolone is a thioquinolone or a sulphinyl or suphonyl derivativesthereof. In one embodiment, the halogenated quinolone is flosequinan(7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone).

[0016] In one embodiment, the method comprises a) providing: i) apatient (whether male or female) suffering from symptoms of sexualdysfunction who is free from cardiac disease; and ii) flosequinan; andb) introducing said flosequinan to said patient such that such symptomsarc reduced.

[0017] In another embodiment, the method comprises a) providing: i) apatient (whether male or female) suffering from symptoms of sexualdysfunction who is not being treated (and/or has not been treated in thepast) with a drug that causes hypotensive effects, and ii) flosequinan;and b) introducing said flosequinan to said patient such that suchsymptoms are reduced.

[0018] In another embodiment, the method comprises a) providing: i) apatient (whether male or female) suffering from symptoms of sexualdysfunction who is not being treated (and/or has not been treated in thepast) with a nitrite or nitrate, and ii) flosequinan; and b) introducingsaid flosequinan to said patient such that such symptoms are reduced.

[0019] In one embodiment, the method comprises providing: i) a male witherectile dysfunction, and ii) flosequinan; and introducing saidflosequinan to said male such that an erection is produced.

[0020] It is not intended that the present invention be limited by themethod of introduction of flosequinan. In one embodiment, theflosequinan is introduced into said male orally. In a preferredembodiment, the male is an adult human and the oral dosage is in asingle dose per day of fifty to seventy-five milligrams. In otherembodiments said flosequinan is introduced cutaneously, transurethrally,by standard injection and intracavernosally.

[0021] The present invention is not limited by the degree of response bythe male subject. In one embodiment, the erection induced is sufficientfor vaginal penetration.

[0022] Likewise, the present invention also contemplates the use ofsexual stimulation in addition to the application of a pharmaceuticalcomposition. For example, one embodiment comprises a) providing: i) amale, having a penis, with erectile dysfunction, and ii) flosequinan,iii) sexual stimulation; and b) introducing said flosequinan and sexualstimulation to said male such that an erection is produced.

[0023] Likewise, the present invention is not limited by the nature ofthe sexual stimulation. In one embodiment, the sexual stimulation issexually explicit media. In another embodiment, the sexual stimulationinvolves manipulation of the penis, such as with vibration.

[0024] It is not intended that the present invention be limited by thenature of the formulation. In one embodiment, the present inventioncontemplates a formulation comprising a quinoline or derivative thereofin a mixture comprising lactose.

DEFINITIONS

[0025] As used herein, the term “quinoline” refers to chemicalcompositions comprising quinoline as set forth in the followingstructure:

[0026] as well as other forms of quinoline, (e.g., isoquinoline):

[0027] As used herein, the phrase “derivatives of quinoline” refers tochemical compositions comprising quinoline with a chemical groupattached, including halogenated quinoline, e.g., 5-bromoquinoline:

[0028] and 1-methylisoquinoline:

[0029] As used herein, the phrase “methylsulphinyl derivatives ofquinoline” refers to chemical compositions comprising quinoline with amethylsulphinyl group attached. Examples include flosequinan(7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone):

[0030] and sulfone metabolites of flosequinan:

[0031] As used herein, a patient who is “free from cardiac disease” anda patient who is “free from symptoms of cardiac disease” indicate thatthe patient has not been diagnosed with angina, myocardial infarction,congestive heart failure and that symptoms of angina, ischemia,myocardial infarction, congestive heart failure have not been detected,respectively.

[0032] As used herein, “drugs that have hypotensive effects” are thosedrugs which, when administered, cause the patient's end-diastolic bloodpressure to be reduced. Nitrates are commonly used drugs which havehypotensive effects.

[0033] As used herein, “nitrates” are compounds that contain the —NO₂—moiety. Nitrates typically used in the clinic are shown in the attachedtable.

[0034] As used herein, the term “erectile dysfunction” refers to certaindisorders of the cavernous tissue of the penis and the associated faciawhich produce impotence, the inability to attain a sexually functionalerection;

[0035] As used herein “standard injection” refers to the placement of apharmaceutical composition into a subject (e.g., with a hypodermicneedle). For example, such injection can be made subcutaneously,intravenously, intramuscularly, intracavernosally, etc. TABLE 1NONPROPRIETARY NAMES AND TRADE CHEMICAL PREPARATIONS, USUAL DOSES, ANDNAMES STRUCTURE ROUTES OF ADMINISTRATION* Amyl nitrite (isoamyl nitrite)

Inh: 0.18 or 0.3 ml, inhalation Nitroglycerin (glyceryl trinitrate;NITRO-BID, NITROSTAT, NITROL, NITRO-DUR, others)

T: S: C: B: O:  D: IV: 0.15 to 0.6 mg as needed 0.4 mg per spray asneeded 2.5 to 9 mg two to four times daily 1 mg every 3 to 5 h 1.25 to 5cm (½ to 2 in.), topically to skin every 4 to 8 h 1 disc (2.5 to 15 mg)every 24 h 5 μg/min; increments of 5 μg/min Isosorbide dinitrate(ISORDIL, SORBITRATE, DILATRATE, others)

T: T(C): T(O): C: 2.5 to 10 mg every 2 to 3 h 5 to 10 mg every 2 to 3 h10 to 40 mg every 6 h 40 to 80 mg every 8 to 12 hIsosorbide-5-mononitrate (IMDUR, ISMO, others)

T: C: 10 to 40 mg twice daily 60 mg daily Erythrityl tetranitrate(CARDILATE)

T: T(O): 5 to 10 mg as needed 10 mg three times daily

[0036] As used herein, “intracavernosal” injection is injection into thecorpus cavernosum of the penis.

[0037] As used herein, an “erection” refers to the condition of a peniswhereby it is at least semi-rigid as opposed to being in a flaccidstate.

[0038] As used herein, “by oral administration” refers to theintroduction of a pharmaceutical composition into a subject by way ofthe oral cavity (e.g., in aqueous liquid or solid form).

[0039] As used herein, “cutaneously” refers to the introduction of apharmaceutical composition into a subject by application to the surfaceof the skin such that the composition is absorbed into the subject.

[0040] As used herein, “transurethrally” refers to the introduction of apharmaceutical composition to the urethra of a subject such that thecomposition is absorbed into the subject.

[0041] As used herein, “sufficient for vaginal penetration” refers tothe state of an erection such that the penis is capable of entering avagina without manual manipulation.

[0042] As used herein, “sexual stimulation” refers to activity thatwould induce an erection in a male without erectile dysfunction (e.g.,sexually explicit media, manual manipulation, vibration, live eroticentertainment, etc.)

[0043] As used herein, “sexually explicit media” refers to films,videos, books, magazines, etc. that depict sexual activity.

[0044] As used herein “single dosage” refers to a pharmaceuticalcomposition of a formulation that is capable of achieving its intendedeffect in a single application.

DETAILED DESCRIPTION OF THE INVENTION

[0045] The present invention provides relates to methods for thetreatment of sexual dysfunction in males and females (including but notlimited to erectile dysfunction in males) in particular treatmentgroups. The methods of the present invention comprise the utilization ofpharmaceutical compositions to patients who are free of symptoms ofcardiac disease and who have not been treated with drugs which causehypotensive effects, such as nitrites and nitrates. The compositionscomprise quinolines and quinolones, including derivatives thereof.

[0046] In one embodiment flosequinan is administered. Importantly,flosequinan may potentiate the hypotensive effects of nitrates, and itsadministration to patients who are concurrently using organic nitratesin any form may be contraindicated.

[0047] In one embodiment, the present invention contemplates the use ofcompositions that are effective to induce an erection in a human malesuffering from impotence of any origin, other than anatomicaldeficiencies (i.e., lacking a penis or a significant portion thereof)that preclude an erection sufficient for vaginal penetration. Inparticular, these compositions may be used to induce an erection in amale suffering from impotence caused by severe atherosclerosis, and alsoimpotence that is neurogenic or psychogenic in origin. The compositionsutilized in the methods of the present invention comprise quinolines andquinolones, including derivatives thereof.

[0048] While the present invention is not limited by the nature of thederivatives, in one embodiment, the present invention encompasses theuse of a variety of quinoline derivatives (e.g., 5-bromoquinoline,5-nitroisoquinoline, 8-nitroisoquinoline and 1-methylisoquinoline). Oneskilled in the art can readily produce such derivatives as set forth inMcMurry, Organic Chemistry, 2nd Ed., Brooks/Cole Publishing, Belmont,Calif. (1988), pages 1044-1045 and 1076.

[0049] In another embodiment, the present invention contemplates the useof methylthio and methylsulphinyl derivatives of quinoline. In apreferred embodiment, the methylsulphinyl derivative is flosequinan(7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone).

[0050] Methods of producing methylsuphinyl and methylthio derivatives ofquinoline, including flosequinan, are set forth in U.S. Pat. Nos.5,079,264 and 5,011,931 to MacLean et al., hereby incorporated byreference. While it is not necessary to understand any particularmechanism to carry out the present invention, it is believed that insome circumstances flosequinan can act as a direct-acting vasodilator torelax the corpus cavernosum smooth muscle cells, which in turn increasesblood flow into the cavernosa space. This then leads to increasedcavernosa pressure to produce an erect penis.

[0051] The action of flosequinan in the body is not preciselyunderstood. Its activity in the body is attributed to flosequinanitself, as well as its sulfone metabolite. It has been reported to beuseful to some degree in the treatment of heart failure. [See Kelso etal., J. Cardiovasc. Pharmacol. 25:376 (1995)]. However, its actionappears to have little effect in patients with end-stage failure[Perreault et al., Br. J. Pharmacol. 106:511 (1992)] and does not affectmortality or arrhythmias following coronary artery ligation [Jones etal., Br. J. Pharmacol. 108:1111(1993)].

[0052] Likewise, flosequinan has been reported to be a selectiveinhibitor of phosphodiesterase III [Gristwood et al., Br. J. Pharmacol.105:985 (1992)]. [Frodsham et al., Eur. J. Pharmacol. 211:383 (1992)],however, report that the phosphodiesterase inhibition of flosequinan, asrelevant to its efficacy in heart failure, is questionable. Thus, theapplication of flosequinan to particular purposes in the body is notwell-characterized and must be determined empirically.

[0053] Diagnosis of Male Erectile Dysfunction

[0054] Determination whether a human male is suffering from impotencethat is substantially only neurogenic or psychogenic is readily made bya person skilled in the art using a number of readily availablediagnostic procedures. Thus, a male suffering from impotence can firstbe given a physical examination with particular attention to possiblepenile and scrotal pathology, whereby any anatomical deficiencyprecluding an erection sufficient for vaginal penetration can bedetected. In the absence of such an anatomical deficiency, the male canbe subjected to tests, whereby penile venous leakage or severe oruntreatable atherosclerosis can be detected.

[0055] Such tests include determination of the penobrachial bloodpressure index (PBPI), doppler investigation of the penile arteries, anda papaverine test. The PBPI is the penile systolic blood pressuredivided by the systolic blood pressure determined at one of the arms.These blood pressures can be determined by any number of standardtechniques. Thus, the penile systolic blood pressure can be determinedby i) placing an inflatable cuff around the base of the free part of thepenis in the flaccid state which is capable of being used to applyvariable pressure, readable from a gauge, to an object around which thecuff is placed, ii) localizing the penile arteries with a Dopplerultrasound probe (e.g., 8 MHz probe, such as the Mini Doplex D500available from Huntleigh Technology, Luton, United Kingdom), and theniii) inflating and deflating the cuff and ascertaining the pressure atwhich the Doppler sound reappears.

[0056] The pressure at which the Doppler sound reappears is the penilesystolic blood pressure. A male's penile blood pressure is regarded asnormal if his PBPI is >0.80. With regard to Doppler investigation, eachof the two penile cavernous arteries is investigated distal to theaforementioned cuff using the Doppler ultrasound problem. The functionof each of the two arteries is assessed by Doppler ultrasound using anarbitrary scale of 0, 1, 2 or 3, where 0 means that the function is sodeficient that the artery cannot be located and 3 means that the arteryis well enough that maximal Doppler sound is observed.

[0057] In the papaverine test, a tourniquet is placed at the base of thefree part of the penis and tightened and then, with the patient seated,30 mg of papaverine in 1 ml of a physiologically acceptable fluid (e.g.,physiological saline or phosphate-buffered saline) is injected into thepenile cavernous body. In persons suspected of having impotence due to asuprasacral nerve lesion or a psychogenic dysfunction, only 15 mg ofpapaverine is administered, because of the high incidence ofpapaverine-induced priapism in such cases.

[0058] Five minutes after the injection, the tourniquet is removed andan ultrasound Doppler investigation of the penile cavernous arteries iscarried out as described above. The function of the arteries is regardedas normal if both of them score a 3 on the arbitrary scale. After theDoppler investigation, penile vibration, at about a 4 Hz with anamplitude of about 1.2 mm (carried out with, e.g., a Vibrector, fromMulticept, Gentofte, Denmark) is carried out for five to ten minutes andthen erectile response is evaluated.

[0059] Erectile response is classified as full rigidity, if the anglebetween the penis and the legs in the standing position is >90°, andtumescence or no response if the angle is less than or equal to 45°. Animpotent male, who does not have an anatomical deficiency that wouldpreclude having an erection sufficient for vaginal penetration, who hasa PBPI >0.80, who has scores of 2 or 3 in Doppler ultrasoundinvestigations of both of the cavernous arteries of the penis, afterpapaverine injection as described above, and who has a fully rigiderection after papaverine injection and vibration as described above, issuffering from impotence that is “substantially only neurogenic orpsychogenic” in origin.

[0060] It is possible that atherosclerosis or venous leakage contributesto such impotence, and atherosclerosis likely does contribute if thescore is less than 3 in the Doppler investigation of one or both of thecavernous arteries after papaverine injection; but any venous leakage oratherosclerosis in such impotence is not untreatable and, consequently,is not a substantial factor in the impotence and such atherosclerosis,if any, is less than severe.

[0061] Impotence, which is a side-effect of drugs such as beta-blockers,is deemed to be neurogenic impotence in the present specification.Similarly, impotence which is a result of alcoholism or excessiveconsumption of alcohol, is deemed to be neurogenic or psychogenicimpotence, for purposes of the present specification. Thus, a male whois diagnosed in accordance with the present specification as sufferingfrom impotence that is “substantially only neurogenic or psychogenic” inorigin is suffering from impotence that is substantially onlyneurogenic, psychogenic or neurogenic and psychogenic in origin, eventhough an underlying cause of the impotence has been identified as aside-effect of a drug, alcoholism or excessive consumption of alcohol.

[0062] Generally, a male with a PBPI less than about 0.60, with scoresof 0 in Doppler investigations of both penile cavernous arteries (afterpapaverine injection as described above), and with a less than fullyrigid erection after papaverine injection and vibration will haveimpotence caused by “untreatable” atherosclerosis. Methods are availableto ascertain whether impotence is untreatable because of venous leakage.

[0063] One method of ascertaining whether untreatable venous leakage isa cause of impotence is by cavernosometry, optionally supplemented withcavernosography. [See, e.g., Delcour et al., Radiology 161:799 (1986);Porst et al., J. Urol. 137:1163 (1987); Lue et al., J. Urol. 37:829(1987)]. Cavernosometry can be done using, both before and afterintracavernosal injection of 60 mg of papaverine (in 1 ml ofphysiological saline), infusion of physiological saline through a19-gauge needle into one corpus cavernosum with a 21-gauge needleinserted into the other corpus cavernosum for measurement ofintracorporal pressure (which is recorded on a plotter).

[0064] The infusion rates needed to induce and maintain an erection aremeasured. If the infusion rate needed to maintain an erection is greaterthan 50 ml/min before administration of the papaverine and greater than15 ml/min after administration of the papaverine, untreatable venousleakage is present. As long as an erection can be achieved at some flowrate less than about 100 m/min before injection of the papaverine andless than about 50 ml/min after the injection of papaverine, it might bepossible, using cavernosography, to locate the venous lesion associatedwith the leakage, and thereby confirm the diagnosis based oncavernosometry and provide information for possible surgical correctionfor the leakage. In the cavernosography, the penis is X-rayed, bothbefore and after intracavernosal injection of 60 mg papaverine (in 1 mlof physiological saline), while infusing contrast medium into the corpuscavernosum (e.g., through a 19-gauge needle) at a flow rate thatmaintains an erection during the x-raying. Numerous contrast mediasuitable for the procedure are available in the art; these are typicallyaqueous solutions of iodinated compounds that provide between about 180mg/ml and about 360 mg/ml of iodine. Examples are a solution of iohexolproviding 240 mg/ml of iodine sold by Winthrop Pharmaceuticals, NewYork, N.Y., USA, and a solution of iopamidol providing 300 mg/ml iodinesold by Astra Meditec, Goteborg, Sweden. Typically 50-100 ml of thecontrast medium will be employed for each x-ray (i.e., before and thenafter the injection of papaverine). In the cavernosometry andcavernosography, 30 mg papaverine (in 1 ml physiological saline) coupledwith stimulation by vibration can be employed in place of 60 mgpapaverine (in 1 ml physiological saline).

[0065] Treatment of Male Erectile Dysfunction

[0066] It is not intended that the present invention be limited by theparticular nature of the therapeutic preparation. For example, thequinolines or quinolone derivatives (e.g., flosequinan) can be providedtogether with physiologically tolerable liquid, gel or solid carriers,diluents, adjuvants and excipients. In addition, quinoline or quinoloneanalogs may be used together with other chemotherapeutic agents. On theother hand, formulations may also contain such normally employedadditives as binders, fillers, carriers, preservatives, stabilizingagents, emulsifiers, buffers and excipients as, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, cellulose, magnesium carbonate, and the like. Thesecompositions typically contain 1%-95% of active ingredient, preferably2%-70%.

[0067] The present invention is not limited by the method ofintroduction of the therapeutic compound to the body. Among othermethods, the present invention contemplates administering cutaneously,orally, intracavernosally, transurethrally or by standard injection.

[0068] Oral administration of flosequinan is effective, with a meanabsolute bioavailability of 72% following a single does of fiftymilligrams. Peak plasma concentrations of flosequinan are observed 1-2hours following oral administration, while peak metabolite plasma levelsare observed about seven hours following oral dosage. While the presentinvention is not limited to a specific dosage level, for adult humans,in one embodiment the dosage is a single dosage per day of 50milligrams, while in another embodiment the dosage is a single dosageper day of 75 milligrams.

[0069] Flosequinan is water soluble and is soluble in many organicsolvents. Thus, while the present invention is not limited by the formof oral administration, aqueous and organic solution of flosequinan fororal administration is contemplated. Likewise, flosequinan can beassociated with a solid pharmaceutical carrier for solid oraladministration (i.e., in pill form). One skilled in the art is able toreadily prepare such solid formulations, and in one embodiment, theinactive ingredients include croscarmellose sodium, hydroxypropylmethylcellulose, lactose, magnesium stearate, methocel E5,microcrystalline cellulose, povidine, propylene glycol and titaniumdioxide.

[0070] Flosequinan may also be administered cutaneously in a carrieradapted for topical administration. Such carriers include creams,ointments, lotions, pastes, jellies, sprays, aerosols, bath oils, orother pharmaceutical carriers which accomplish direct contact betweenflosequinan and the pore of the skin. In general pharmaceuticalpreparations may comprise from about 0.001% to about 10%, and preferablyfrom about 0.01 to 5% by w/w of the active compound (e.g., flosequinan)in a suitable carrier. In some cases it may be necessary to dissolve theflosequinan in an appropriate solvent such as ethanol or DMSO(dimethylsulfoxide), and the like, to facilitate incorporation into apharmaceutical preparation. Likewise, the present invention can beincorporated in other products associated with sexual activity. Forexample, a coated, erection inducing condom as disclosed in U.S. Pat.No. 4,829,991, hereby incorporated by reference, and can be utilizedwith flosequinan or flosequinan in a pharmaceutical carrier as describedabove.

[0071] While the present invention is not limited by a specific methodof introducing flosequinan intracavernosally, injection of flosequinancan be carried out by any conventional injection means (e.g., employingan hypodermic syringe and needle or a similar device such as theNovolinPen. sold by Squibb-Novo, Inc., Princeton, N.J., USA). Thisinjection may be by subject injecting himself or by another person (suchas a partner during sexual relations or a physician prior to sexualrelations) injecting the male whose erection is to be induced. Methodsfor intracavernosal injection are described in U.S. Pat. No. 5,447,912to Gerstenberg et al., hereby incorporated by reference.

[0072] Flosequinan can be introduced intracavernosally in aphysiologically acceptable composition. Such compositions are aqueoussolutions that are physiologically acceptable for administration byintracavernosal injection into the penis. The physiologically acceptablecarrier is selected such that it is not painful or irritating uponintracavernosal injection. The physiologically acceptable compositionswill preferably be sterile at the time of administration byintracavernosal injection.

[0073] Among the physiologically acceptable compositions for use in themethods is physiological saline or phosphate buffered saline, in whichflosequinan is dissolved or suspended, such that the resultingcomposition is suitable for intracavernosal injection. Such aphysiologically acceptable composition can also include a non-irritantpreservative, such as, e.g., benzalkonium chloride at 0.05% (w/v) to0./2% (w/v). As the skilled artisan will understand, there are numerousnon-toxic salts of VIP, PHM and α-adrenergic blockers that can beemployed in a physiologically acceptable composition for use in themethods herein, including, among others, the chloride, bromide, acetate,sulfate, and mesylate salts.

[0074] In carrying out the methods, it is preferred that, for a periodof time between about 1 minute and about 15 minutes (preferably about 5minutes-10 minutes), the penis is constricted near the base thereof andbetween the base and the point at which the injection into a corpuscavernosum occurs, in order to limit loss of injected fluid from thecorpus cavernosum before the ingredients in the fluid, that are activein inducing erection, have been able to have erection-inducing effects.The constriction can be effected by any means known in the art, such aswith a tourniquet, cuff, rubber band or the like, or even manually, inorder to slow the release of the injected fluid and thepharmacologically active substance(s) therein into the generalcirculation.

[0075] Likewise, the present invention is not limited by a particularmethod for introducing flosequinan transurethrally. In one embodiment,flosequinan is introduced to the urethra in a carrier as described forcutaneous administration. Devices and methods for transurethralintroduction of pharmaceutical compositions is described in U.S. Pat.No. 5,474,535 to Place et al.; Voss, U.S. Pat. No. 4,801,587 and Kock,EPA 0357581, all hereby incorporated by reference.

[0076] Additional methods of introducing flosequinan transurethrallyinclude the use of medicated catheters, such as those used to prevent ortreat localized infections and irritation of the urethra and bladder(See U.S. Pat. No. 4,640,912, hereby incorporated by reference).Alternatively, transurethral administration of pharmaceuticalcompositions is presented in U.S. Pat. Nos. 4,478,822, 4,610,868,4,640,912 and 4,746,508, all hereby incorporated by reference, andmedicated urethral suppositories, inserts or plugs, typically containinganti-infective agents or spermicide are disclosed in U.S. Pat. Nos.1,897,423, 2,584,166, 2,696,209 and 3,373,746, all incorporated byreference.

[0077] While the present invention is not limited to the method ofinjecting flosequinan, in the preferred embodiment, it is injected witha standard syringe. One skilled in the art would be capable of injectingflosequinan with a carrier as described for intracavernosal injection.

[0078] In one embodiment, the administration of the compositions of thepresent invention is accompanied by sexual stimulation to induce anerection. The sexual stimulation can begin before or after theintroduction of flosequinan. If the stimulation begins after theinjection, it is preferably begun within 5 to 10 minutes to insure thatthere is significant overlap of the pharmacological effects of thepharmaceutical composition administered and the stimulative effects ofthe sexual stimulation. Whether the stimulation begins before or afterthe injection, it will continue preferably at least until an erectionsufficient for vaginal penetration is achieved.

[0079] Sexual stimulation as prescribed by these methods, includes anyform of sexual stimulation that would induce an erection in a normalmale who is not suffering from erectile insufficiency. The sexualstimulation can be that which occurs in the course of sexual relationsbetween the subject and another person or can be outside sexualrelations with another person. Examples of methods of sexual stimulationinclude, alone or in combination, touching or erotically manipulatingerogenous areas of the genital organs or other erogenous parts of thebody; providing visual stimulation, as with a sexually explicit media(e.g., pornographic film) or other form of sexually stimulative show ordisplay. Additionally, providing vibratory stimulation to the penis, atbetween about 30 Hz and about 100 Hz with an amplitude of about 1 mm toabout 5 ram, as can be provided, for example, by resting the penis onthe table of a vibrating apparatus such as that of a Vibrector system(Multicept, Genofte, Denmark).

[0080] In inducing an erection in an impotent male outside of sexualrelations, as, for example, when a physician induces an erection in apatient suffering from psychogenic impotence, a preferred method ofsexual stimulation includes providing visual stimulation, as with apornographic film, simultaneously with vibratory stimulation of thepenis, as with a Vibrector system set to between about 30 Hz and about60 Hz (usually about 50 Hz) in frequency and between about 1 mm andabout 2.5 mm (usually about 2.2 mm) in amplitude.

[0081] From the above, it should be clear that the present inventionprovides methods of treatment of male erectile dysfunction withpharmaceutical agents. In particular, quinolines and quinolones areadministered therapeutically to patients having such dysfunction.

1. A method, comprising: a) providing: i) a subject diagnosed witherectile dysfunction who is free of cardiac disease; and ii) atherapeutic formulation comprising a quinoline; and b) introducing saidformulation to said subject such that an erection is produced.
 2. Themethod of claim 1, wherein said quinoline is a halogenated quinoline. 3.The method of claim 2, wherein said halogenated quinoline isflosequinan.
 4. The method of claim 3, wherein said flosequinan isintroduced into said subject by oral administration.
 5. The method ofclaim 4, wherein said subject is an adult human and said oraladministration comprises up to approximately 100 milligrams offlosequinan.
 6. The method of claim 3, wherein said flosequinan isintroduced into said subject cutaneously.
 7. The method of claim 3,wherein said flosequinan is introduced into said subjecttransurethrally.
 8. The method of claim 3, wherein said flosequinan isintroduced into said subject intracavernosally.
 9. The method of claim1, wherein said subject is a male.
 10. The method of claim 1, whereinsaid subject is a female.
 11. A method, comprising: a) providing: i) asubject diagnosed with erectile dysfunction, wherein said subject is notbeing treated with a drug that causes hypotensive effects; and ii) atherapeutic formulation comprising a quinoline; and b) introducing saidformulation to said subject such that an erection is produced.
 12. Themethod of claim 11, wherein said quinoline is a halogenated quinoline.13. The method of claim 12, wherein said halogenated quinoline isflosequinan.
 14. The method of claim 13, wherein said flosequinan isintroduced into said subject by oral administration.
 15. The method ofclaim 13, wherein said flosequinan is introduced into said subjectcutaneously.
 16. The method of claim 13, wherein said flosequinan isintroduced into said subject transurethrally.
 17. The method of claim13, wherein said flosequinan is introduced into said subjectintracavernosally.
 18. The method of claim 11, wherein said subject is amale.
 19. The method of claim 11, wherein said subject is a female. 20.The method of claim 11, wherein said subject has not been treated in thepast with a drug that causes hypotensive effects.
 21. A method,comprising: a) providing: i) a subject diagnosed with erectiledysfunction, wherein said subject is not being treated with a nitrite ornitrate; and ii) a therapeutic formulation comprising a quinoline; andb) introducing said formulation to said subject such that an erection isproduced.
 22. The method of claim 21, wherein said quinoline is ahalogenated quinoline.
 23. The method of claim 22, wherein saidhalogenated quinoline is flosequinan.
 24. The method of claim 23,wherein said flosequinan is introduced into said subject by oraladministration.
 25. The method of claim 23, wherein said flosequinan isintroduced into said subject cutaneously.
 26. The method of claim 23,wherein said flosequinan is introduced into said subjecttransurethrally.
 27. The method of claim 23, wherein said flosequinan isintroduced into said subject intracavernosally.
 28. The method of claim21, wherein said subject is a male.
 29. The method of claim 21, whereinsaid subject is a female.
 30. The method of claim 21, wherein saidnitrate is selected from the group consisting of glyceryl trinitrate,isosorbide dinitrate, isosorbide-5-mononitrate and erythrityltetranitrate.